Multiple testing treatments

In some circumstances it may be necessary to combine several events/endpoints to produce a combined or composite endpoint. The main purpose in doing this is to again avoid multiple testing and more will be said about this in Chapter 10. In addition, combining endpoints/events will increase the absolute numbers of events observed and this can increase sensitivity for the detection of treatment effects. 

The problem with this so-called multiplicity or multiple testing arises when we make a claim on the basis of a positive result which has been generated simply because we have undertake lots of comparisons. Inflation of the type I error rate in this way is of great concern to the regulatory authorities they do not want to be registering treatments that do not work. It is necessary therefore to control this inflation. The majority of this chapter is concerned with ways in which the potential problem can be controlled, but firstly we will explore ways in which it can arise. 

In the case of multiple treatment groups it is important to recognise the objectives of the trial. For example, in a three-arm trial with test treatment, active comparator and placebo, the primary objective may well be to demonstrate the effectiveness... 

The interpretation of the pharmacokinetic variables Cmax, AUCs and MRT of insulin glulisine was based on 95 % confidence intervals, after ln-transformation of the data. These 95 % confidence intervals were calculated for the respective mean ratios of pair-wise treatment comparisons. In addition, the test treatment was compared to the reference treatment with respect to the pharmacokinetic variables using an ANOVA with subject, treatment and period effects, after ln-transformation of the data. The subject sum of squares was partitioned to give a term for sequence (treatment by period interaction) and a term for subject within sequence (a residual term). Due to the explorative nature of the study, no adjustment of the a-level was made for the multiple testing procedure. 

Figure 10. Reduction in floor echoes obtained using multiple coating treatment. Performance is for one particular downward-looking test geometry and includes some multiple reflections.

Suppose that an investigational antihypertensive drug is evaluated at multiple doses in a parallel-group placebo-controlled study. Participants in this therapeutic exploratory study were randomly assigned to receive either placebo or one of three possible doses of the test treatment (low, medium, or high). The treatment period was for 6 weeks. The number and percentage of participants experiencing any AE, and particular AEs, are displayed in Table 8.2. 

It should be noted that these are not the only acceptable methods applicable to multiple comparisons from an ANOVA. In each individual case, the choice among possible approaches is largely dependent on the study design. For example, Dunnett s test can be used when the only comparisons of interest are each test treatment versus a control (for example, in a placebo-controlled, dose-ranging study). Like Tukey s test, Dunnett s method is more powerful than Bonferroni s. In general, other methods gain power compared with Bonferroni s method by... 

Sparks PJ, Daniell W, Black DW, et al Multiple chemical sensitivity syndrome a clinical perspective, II evaluation, diagnostic testing, treatment, and social considerations. J Occup Med 36 731-737, 1994b... 

For example, the outcome Y might be multivariate and Vo(/) might represent the estimand for the causal effect of treatment A(0) on outcome Y j). Under the asymptotic linearity assumption on / , we have -ipo) M(0,2 ), where is the empirical covariance matrix of the estimated influence curve vectors ZC (0,)GM . This allows the construction of a simultaneous confidence interval for )Ao of the form tp ( ) Co.95 l n(j, j) /-Jn, where C095 is the 0.95-quantile of maxy Z(j) with Z N(0, p,, where p is the correlation matrix of The single-step multiple testing procedure is now defined as follows reject Ho( ) if T j) = yfn ) j)l>Co,95- This confrols the family-wise... 

Several researchers experimented with electrochemically driven techniques. Budd and Booth used a potentiostatic approach [23]. Others have tried impressed current tests. Although both appeared promising, these procedures did not lend themselves to the multiple testing required for production control of heat treatment. Neither type of test has been standardized to date. 

Proteasomal inhibition represents a novel strategy in cancer treatment and the small molecule Bortezomid (PS-341, Velcade ) has been approved for the treatment of refractory and relapsed multiple myeloma, a proliferative disease of plasma cells. Bortezomid inhibits an active site in a proteasome subunit and remarkably shows selective cytotoxicity to cancer cells. Although the underlying mechanisms are not completely understood bortezomid apparently induces a cell stress response in these tumor cells followed by caspase-dependent apoptosis. Whether bortezomid is beneficial for the treatment of other proliferative disease is currently being tested in clinical trials. 

Those with type 1 diabetes mellitus produce insulin in insufficient amounts and tiierefore must have insulin supplementation to survive Type 1 diabetes usually has a rapid onset, occurs before die age of 20 years, produces more severe symptoms tiian type 2 diabetes, and is more difficult to control. Major symptoms of type 1 diabetes include hyperglycemia, polydipsia (increased thirst), polyphagia (increased appetite), polyuria (increased urination), and weight loss. Treatment of type 1 diabetes is particularly difficult to control because of the lack of insulin production by die pancreas. Treatment requires a strict regimen tiiat typically includes a carefully calculated diet, planned physical activity, home glucose testing several times a day, and multiple daily insulin injections. 

Often there is a desire to compare responses to multiple treatments rather than simply evaluate active against a placebo control. For instance, it may be useful to evaluate several doses or to assess a product against another marketed product. Increasing the number of treatments will increase the sample size required overall, but will also increase the number of subjects required per treatment arm because the number of statistical comparisons is larger. If all between-group comparisons are to be made, the number of statistical tests increases dramatically as the number of treatment arms increases. With two groups, only one comparison is possible. With three groups, the number... 

FIGURE 38-1. Primary assessment and initial treatment for complaint of excessive daytime sleepiness. RLS, restless-legs syndrome NPSG, nocturnal polysomnography OSA, obstructive sleep apnea DA, dopamine agonist MSLT, multiple sleep latency test BZDRA, benzodiazepine receptor agonist SNRI, serotonin and norepinephrine reuptake inhibitor TCA, tricyclic antidepressant CPAP, continuous positive airway pressure. 

The dry weights (104 C, 48 hr) of ten plants from each treatment group were taken at the termination of each experiment in order to compare growth effects with plant water status. Dry weight data were analyzed using analysis of variance (ANOVA) and Duncan s multiple-range test. Diffusive resistance and water potential were evaluated using the t-test. Each of these and subsequent experiments was replicated. 

Values are the means of 15 plants harvested 7 days after treatment. Means In each column followed by the same letter are not significantly different at the 5% level of probability using Duncan s Multiple Range test. 

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